Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA.
BMC Genomics. 2024 Aug 28;25(1):809. doi: 10.1186/s12864-024-10730-3.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that disrupts hepatic function leading to steatotic liver disease (SLD)-like pathologies, such as steatosis, steatohepatitis, and fibrosis. These effects are mediated by the aryl hydrocarbon receptor following changes in gene expression. Although diverse cell types are involved, initial cell-specific changes in gene expression have not been reported. In this study, differential gene expression in hepatic cell types was examined in male C57BL/6 mice gavaged with 30 µg/kg of TCDD using single-nuclei RNA-sequencing. Ten liver cell types were identified with the proportions of most cell types remaining unchanged, except for neutrophils which increased at 72 h. Gene expression suggests TCDD induced genes related to oxidative stress in hepatocytes as early as 2 h. Lipid homeostasis was disrupted in hepatocytes, macrophages, B cells, and T cells, characterized by the induction of genes associated with lipid transport, steroid hormone biosynthesis, and the suppression of β-oxidation, while linoleic acid metabolism was altered in hepatic stellate cells (HSCs), B cells, portal fibroblasts, and plasmacytoid dendritic cells. Pro-fibrogenic processes were also enriched, including the induction retinol metabolism genes in HSCs and the early induction of anti-fibrolysis genes in hepatocytes, endothelial cells, HSCs, and macrophages. Hepatocytes also had gene expression changes consistent with hepatocellular carcinoma. Collectively, these findings underscore the effects of TCDD in initiating SLD-like phenotypes and identified cell-specific gene expression changes related to oxidative stress, steatosis, fibrosis, cell proliferation and the development of HCC.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种持久性环境污染物，可破坏肝脏功能，导致脂肪性肝病（SLD）样病变，如脂肪变性、脂肪性肝炎和纤维化。这些影响是通过芳香烃受体介导的，随后基因表达发生变化。尽管涉及多种细胞类型，但尚未报道初始细胞特异性基因表达变化。在这项研究中，使用单核 RNA 测序，用 30µg/kg 的 TCDD 灌胃雄性 C57BL/6 小鼠，检查了肝实质细胞类型中的差异基因表达。鉴定了 10 种肝实质细胞类型，大多数细胞类型的比例保持不变，除了中性粒细胞在 72 小时增加。基因表达表明，TCDD 早在 2 小时就诱导了与肝细胞氧化应激相关的基因。肝细胞、巨噬细胞、B 细胞和 T 细胞中的脂质稳态受到破坏，特征是诱导与脂质转运、类固醇激素生物合成相关的基因，并抑制β-氧化，而肝星状细胞（HSCs）、B 细胞、门脉成纤维细胞和浆细胞样树突状细胞中的亚油酸代谢发生改变。促纤维化过程也被富集，包括 HSCs 中视黄醇代谢基因的诱导和肝细胞、内皮细胞、HSCs 和巨噬细胞中抗纤维化基因的早期诱导。肝细胞也有与肝细胞癌一致的基因表达变化。总之，这些发现强调了 TCDD 引发 SLD 样表型的作用，并确定了与氧化应激、脂肪变性、纤维化、细胞增殖和 HCC 发展相关的细胞特异性基因表达变化。
